Paroxetine (I) and femoxetine (II) are closely related serotonin (5-hydroxytryptamine) reuptake inhibitors which have been used clinically for the treatment of depression. (S. M. Hassan et al., Brit. J. Clin. Pharmacol., 19, 705, 1985; L. E. Dahl et al., Acta Psychiatr. Scand., 66, 9, 1982; P. N. Reebye et al., Pharmacopsychiatria, 15, 164, 1982). U.S. Pat. No. 3,912,743 delineates some of paroxetine's and femoxetine's pharmacological properties. ##STR1##
The stereochemical configurations at the C-3 and C-4 positions of the piperidine ring are critical for the activity of these compounds. For paroxetine, the stereochemistry is 3-S, 4-R and for femoxetine, the stereochemistry is 3-R, 4-S. The method for obtaining the requisite stereochemistry employs the chiral resolution of an intermediate; specifically the menthyl ester hydrobromide salts III and IV as disclosed in U.S. Pat. No. 4,007,196. ##STR2##
Using the previously described synthesis, no control over the stereochemistry at C-4 was obtained. This resulted in the loss of 50% of the material as the wrong diastereomer which represents a severe disadvantage of the above procedure. This motivated us to find a versatile method to control the stereochemistry at C-3 and C-4. It is pertinent to note that recent literature (M. Amat, J. Hidalgo, and J. Bosch, Tetrahedron Asymmetry. 7, 1996, pp. 1591-1594) also provides a completely different chiral route to the enantiomer of paroxetine.HCl. The overall yield for this 8-step synthesis is 19.7%.